Overexpression of Transcription Factor Sp1 Leads to Gene Expression Perturbations and Cell Cycle Inhibition
Emmanuelle Deniaud,Joël Baguet,Roxane Chalard,Roxane Chalard,Bariza Blanquier,Lilia Brinza,Julien Meunier,Julien Meunier,Marie-Cécile Michallet,Aurélie Laugraud,Claudette Ah-Soon,Anne Wierinckx,Marc Castellazzi,Joël Lachuer,Christian Gautier,Jacqueline Marvel,Yann Leverrier +16 more
TLDR
It is shown that the binding to DNA of overexpressed Sp1 induces an inhibition of cell cycle progression that precedes apoptosis and a transcriptional response targeting genes containing Sp1 binding sites in their promoter or not suggesting both direct Sp1-driven transcription and indirect mechanisms.Abstract:
BACKGROUND: The ubiquitous transcription factor Sp1 regulates the expression of a vast number of genes involved in many cellular functions ranging from differentiation to proliferation and apoptosis. Sp1 expression levels show a dramatic increase during transformation and this could play a critical role for tumour development or maintenance. Although Sp1 deregulation might be beneficial for tumour cells, its overexpression induces apoptosis of untransformed cells. Here we further characterised the functional and transcriptional responses of untransformed cells following Sp1 overexpression. METHODOLOGY AND PRINCIPAL FINDINGS: We made use of wild-type and DNA-binding-deficient Sp1 to demonstrate that the induction of apoptosis by Sp1 is dependent on its capacity to bind DNA. Genome-wide expression profiling identified genes involved in cancer, cell death and cell cycle as being enriched among differentially expressed genes following Sp1 overexpression. In silico search to determine the presence of Sp1 binding sites in the promoter region of modulated genes was conducted. Genes that contained Sp1 binding sites in their promoters were enriched among down-regulated genes. The endogenous sp1 gene is one of the most down-regulated suggesting a negative feedback loop induced by overexpressed Sp1. In contrast, genes containing Sp1 binding sites in their promoters were not enriched among up-regulated genes. These results suggest that the transcriptional response involves both direct Sp1-driven transcription and indirect mechanisms. Finally, we show that Sp1 overexpression led to a modified expression of G1/S transition regulatory genes such as the down-regulation of cyclin D2 and the up-regulation of cyclin G2 and cdkn2c/p18 expression. The biological significance of these modifications was confirmed by showing that the cells accumulated in the G1 phase of the cell cycle before the onset of apoptosis. CONCLUSION: This study shows that the binding to DNA of overexpressed Sp1 induces an inhibition of cell cycle progression that precedes apoptosis and a transcriptional response targeting genes containing Sp1 binding sites in their promoter or not suggesting both direct Sp1-driven transcription and indirect mechanisms.read more
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Sp1 transcription factor: A long-standing target in cancer chemotherapy.
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A non-canonical DNA structure is a binding motif for the transcription factor SP1 in vitro
TL;DR: Data suggest that SP1 is able to bind both, canonical SP1 duplex DNA as well as G-quadruplex structures in vitro and it is hypothesize that both types of interactions may occur in cells.
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MiR-140 is co-expressed with Wwp2-C transcript and activated by Sox9 to target Sp1 in maintaining the chondrocyte proliferation
Jun Yang,Shengying Qin,Chengqing Yi,Gang Ma,Huang Zhu,Wenrong Zhou,Yuyu Xiong,Xuming Zhu,Yujiong Wang,Lin He,Xizhi Guo +10 more
TL;DR: It is detected that miR‐140 was uniquely expressed in chondrocyte and suppressed by Wnt/β‐catenin signalling, and Sp1, the activator of the cell cycle regulator p15INK4b, was identified as a target of miR•140 in maintaining the chondrogenic proliferation.
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MicroRNAs play a role in chondrogenesis and osteoarthritis (Review)
TL;DR: The results of this review indicated that more than 25 miRNAs have been implicated in chondrogenesis and OA, and many are functionally implicated in the pathogenesis of the disease.
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Specificity protein (Sp) transcription factors Sp1, Sp3 and Sp4 are non-oncogene addiction genes in cancer cells
TL;DR: Functional and genomic results coupled with overexpression of Sp transcription factors in tumor vs. non-tumor tissues and decreased Sp1 expression with age indicate that Sp1, Sp3 and Sp4 are non-oncogene addiction (NOA) genes and are attractive drug targets for individual and combined cancer chemotherapies.
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